Method for producing n-ethyl-n-{3-(3-cyanopyrazolo{1,5a}pyrimidine-7-yl)phenyl acetamide

ABSTRACT

N-ethyl-N-[3-(3-cyanopyrazolo[1,5a]pyrimidine-7-yl)phenyl]acetamide (Zaleplon) can be produced by condensing 3-(N-acetyl-N-ethyl-amino)-β-oxo-phenylpropanal sodium salt with 3-amino-4-cyanopyrazole. Said sodium salt can be produced by first treating 3-acetylamino-acetophenone with an alkali metal hydroxide, in particular with powdered potassium hydroxide and then with an ethylating reagent, in particular ethyl bromide and the N-(3-acetylphenyl)-N-ethyl-acetamide that is obtained is reacted with a formic acid alkyl ester in the presence of an alkali metal alkanolate, in particular in the presence of sodium ethanolate. Zaleplon is the active ingredient of the soporific licensed under the trade name Sonata®.

The present invention relates to a novel process for the preparation ofN-ethyl-N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]acetamide offormula III:

This is the active ingredient of the hypnotic authorized under the tradename Sonata®.

The process according to the invention is characterized in that thesodium salt of 3-(N-acetyl-N-ethylamino)-β-oxophenylpropanal of formulaI:

is condensed with 3-amino-4-cyanopyrazole of formula II:

This condensation reaction is conveniently carried out in a mixture ofglacial acetic acid, ethanol, isopropanol, acetone or tetrahydrofuranwith concentrated hydrochloric acid and water. The reaction mediumcomprises preferably about 150 to 500, particularly preferably about 300to 400 and very particularly preferably about 340 parts by weight ofglacial acetic acid, ethanol, isopropanol, acetone or tetrahydrofuran,about 30 to 100, particularly preferably about 45 to 55 and veryparticularly preferably about 50 parts by weight of concentrated (i.e.approx. 37%) hydrochloric acid and about 100 to 400, particularlypreferably about 250 to 300 and very particularly preferably about 270parts by weight of water. A particularly preferred reaction medium is amixture of glacial acetic acid with concentrated hydrochloric acid andwater, especially a mixture comprising about 150 to 500, particularlypreferably about 300 to 400 and very particularly preferably about 340parts by weight of glacial acetic acid, about 30 to 100, particularlypreferably about 45 to 55 and very particularly preferably about 50parts by weight of concentrated (i.e. approx. 37%) hydrochloric acid andabout 100 to 400, particularly preferably about 250 to 300 and veryparticularly preferably about 270 parts by weight of water. By way ofexample, in one possible procedure, about 30 parts by weight of thecompound of formula II are placed in about 340 parts by weight ofglacial acetic acid, about 50 parts by weight of concentrated, i.e.approx. 37%, hydrochloric acid are added at room temperature, then,after cooling to about 5 to 10° C., especially to about 7° C., asolution of about 70 parts by weight of the sodium salt of formula I inabout 270 parts by weight of water is slowly added dropwise,conveniently over about one hour, and the mixture is then stirred forsome time, especially for about one hour, with cooling at around thetemperature mentioned above. About 150 to 800, conveniently about 300 to500 and preferably about 400 parts by weight of water are then added,after which the product can be filtered off, washed with water(conveniently twice with about 150 parts by weight of water each time)and dried, conveniently under vacuum at about 50 to 80° C., especiallyat about 60 to 70° C. The compound of formula III, i.e. zaleplon, canthus be obtained in good yield and purity in the form of a white solid.

The sodium salt of formula I above, used as the starting material, canbe prepared according to the invention by treating3-acetylaminoacetophenone of formula IV:

firstly with an alkali metal hydroxide and then with an ethylatingagent, and then reacting the resultingN-(3-acetylphenyl)-N-ethylacetamide of formula VII:

with an alkyl formate in the presence of an alkali metal alcoholate.

The alkali metal hydroxide used in the first of these two stages isconveniently potassium hydroxide, preferably powdered solid potassiumhydroxide, and the ethylating agent used in conveniently ethyl bromide.This ethylation is preferably carried out in tetrahydrofuran. By way ofexample, in one possible procedure, about 100 parts by weight of3-acetylaminoacetophenone of formula IV and about 45 to 100 parts byweight, preferably about 65 parts by weight, of powdered potassiumhydroxide are dissolved in about 200 to 500 parts by weight, preferablyabout 350 parts by weight, of anhydrous tetrahydrofuran under an inertgas atmosphere, conveniently under a nitrogen atmosphere, and withstirring, and about 100 to 250 parts by weight, preferably about 155parts by weight, of ethyl bromide, optionally diluted withtetrahydrofuran, are then added at about 35 to 50° C., preferably atabout 40 to 45° C. After a number of hours, conveniently about 2 to 15hours and preferably about 5 to 6 hours, the mixture can be cooled toroom temperature and neutralized with aqueous acid, conveniently withdilute hydrochloric acid; the organic phase can then be separated offand concentrated to dryness, after which the residue can be dried e.g.by distilling off the remaining moisture azeotropically by means oftoluene or the like. The compound of formula VII is obtained in highyield (around 95%) and satisfactory purity (about 80 to 92%) in the formof an oil.

In the second of the two stages of the preparation of the sodium salt offormula I, the alkali metal alkanolate and alkyl formate used areconveniently sodium ethylate and ethyl formate respectively. Again thereaction is conveniently carried out in tetrahydrofuran. By way ofexample, in one possible procedure, about 60 to 65 parts by weight ofthe oil obtained in the first stage (content about 80 to 92%) aredissolved in about 120 to 400 parts by weight, preferably about 200 to250 parts by weight, of anhydrous tetrahydrofuran, after which about 25to 80 parts by weight, preferably about 35 to 40 parts by weight, ofethyl formate and about 120 to 300 parts by weight, preferably about 160to 170 parts by weight, of an approximately 20 to 25% solution of sodiumethanolate in ethanol are added at room temperature, with stirring.After stirring at room temperature for some hours, conveniently about 1to 24 hours and preferably about 4 to 6 hours, further tetrahydrofurancan optionally be added to the reaction mixture, and the precipitatedproduct, i.e. the sodium salt of formula I, can be filtered off, washed(e.g. twice with about 45 parts by weight of tetrahydrofuran each time)and then dried, conveniently under vacuum at about 40 to 50° C. Thesodium salt of formula I can thus be obtained in good yield in the formof a non-hygroscopic powder.

EP 0 208 864 B1 and U.S. Pat. No. 4,626,538 A describe that zaleplon offormula III above can be prepared by converting3-acetylaminoacetophenone of formula IV above intoN-[3-(3-dimethylamino)-1-oxo-2-propenyl)phenyl]acetamide of formula V:

by reaction with N,N-dimethylformamide dimethylacetal, converting thecompound V into the corresponding N-ethyl compound of formula VI:

with an ethyl halide (e.g. ethyl bromide or iodide), in the presence ofsodium hydride, and condensing the compound VI with3-amino-4-cyanopyrazole of formula II above, under reflux in glacialacetic acid; in a variant of this process, it is also possible tocondense N-[3-(3-dimethylamino)-1-oxo-2-propenyl)phenyl]-acetamide offormula V above with 3-amino-4-cyanopyrazole of formula II above andthen to ethylate the resulting product. According to EP 0 776 898 A1 andU.S. Pat. No. 5,714,607 A, zaleplon is obtained as a purer and moreeasily isolatable product by carrying out the condensation reaction ofthe compounds of formulae VI and II above in a mixture of water andacetic acid rather than in glacial acetic acid, the proportion of waterbeing conveniently about 10 to 85%, preferably about 11 to 75% andespecially 60 to 75%.

Like the known processes discussed above, the process according to theinvention is also ultimately based on 3-acetylaminoacetophenone if onetakes into account the precursors according to the invention that yieldthe sodium salt of formula I above. However, compared with these knownprocesses, the process according to the invention offers the followingsubstantial advantages:

-   -   In the ethylation (IV        VII compared with V        VI), potassium hydroxide is used instead of sodium hydride,        which is considerably more expensive and carries high safety        risks.

Instead of N,N-dimethylformamide dimethylacetal (IV

V) it is possible to use ethyl formate/sodium ethanolate (VII

I), which are substantially better value for money and are available ona larger scale.

The sodium salt of formula I can be isolated very easily as it separatesout of the reaction mixture directly in high yield and purity and cansimply be filtered off.

Whereas zaleplon of formula III obtained by condensing the compounds offormulae VI and II in aqueous glacial acetic acid (cf. EP 0 776 898 A1and U.S. Pat. No. 5,714,607 A) is contaminated, after work-up, witharound 1%, i.e. about 0.8 to 1.3%, of an isomer (forming in an amount ofabout 3 to 6% in the reaction mixture), requiring an expensivepurification, the condensation reaction according to the inventionbetween the compounds of formulae I and II, especially under thepreferred reaction conditions described earlier, and specifically underthe conditions described in Example 2 below, succeeds in minimizing thisby-product to less than 0.1%.

The Examples which follow will illustrate the present invention ingreater detail without in any way limiting its scope.

EXAMPLE 1 a) Synthesis of N-(3-acetylphenyl)-N-ethylacetamide (VII)

100 g (0.564 mol) of 3-acetylaminoacetophenone and then 63.2 g (1.13mol) of powdered potassium hydroxide are dissolved in anhydrous THF (350g) under an N₂ atmosphere, with stirring, and a solution of 154 g (1.41mol) of ethyl bromide in anhydrous THF (180 g) is added at 40-45° C.

After 5-6 h the mixture is cooled to room temperature and neutralized bythe addition of 192.5 g (0.39 mol) of 2 M HCl and 45 g of water. Theorganic phase is separated off and concentrated to dryness and theresidue is then co-distilled a further twice with 175 g of toluene.

This gives 133.4 g (content 82%, yield 94%) of the compound VII in theform of an oil.

b) Synthesis of the Na salt of3-(N-acetyl-N-ethylamino)-D-oxophenylpropanal

62.65 g (content 82%, 0.250 mol) of VII are dissolved in anhydrous THF(220 g), and 37.0 g (0.500 mol) of ethyl formate, followed by 162.1 g(0.500 mol) of a 21% solution of sodium ethanolate in ethanol, are thenadded at room temperature, with stirring.

After stirring for 4-6 h at room temperature, 220 g of THF are added andthe precipitated product is then filtered off (on a suction filter),rinsed with twice 45 g of THF and dried under vacuum at 40-50° C.

This gives 61.16 g (85%) of the compound I in the form of a powder. Thematerial is non-hygroscopic.

EXAMPLE 2 Synthesis ofN-ethyl-N-(3-(3-cyanopyrazolo(1,5-a)pyrimidin-7-yl)phenyl)-acetamide(zaleplon) (III)

49.8 g (505 mmol) of 37% hydrochloric acid are added at room temperatureto a solution of 30.0 g (275 mmol) of II in 340 g of glacial aceticacid, the mixture is cooled to 7° C. and a solution of 69.0 g (content93%, 251 mmol) of I in 270 g of water is added dropwise over 1 h. Afterstirring for 1 h in the cold, 400 g of water are added and this isfollowed by filtration (on a suction filter) and washing with twice 150g of water. The product is dried under vacuum at 60-70° C. to give 69.6g (88%) of the compound III in the form of a white solid.

1. A process for the preparation ofN-ethyl-N-[3-(3-cyanopyrazolo[1,5-a]-pyrimidin-7-yl)phenyl]acetamide offormula III:

comprising the step of condensing the sodium salt of3-(N-acetyl-N-ethylamino)-β-oxophenyl-propanal of formula I:

with 3-amino-4-cyanopyrazole of formula II:


2. The process of claim 1, wherein the condensation reaction is carriedout in a reaction medium comprising a mixture of: a. a solvent selectedfrom the group consisting of glacial acetic acid, ethanol, isopropanol,acetone, and tetrahydrofuran; b. concentrated hydrochloric acid; and c.water.
 3. The process of claim 2 wherein, the solvent is of about 150 toabout 500 parts by weight; the concentrated hydrochloric acid is ofabout 150 to about 500 parts by weight; and the water is of about 100 toabout 400 parts by weight.
 4. The process of claim 2, wherein thereaction medium comprises a mixture of: a. glacial acetic acid; b.concentrated hydrochloric acid; and c. water.
 5. The process of claim 4,wherein the reaction medium is mixture of about 150 to about 500 partsby weight of glacial acetic acid, about 30 to about 100 parts by weightof concentrated hydrochloric acid and about 100 to about 400 parts byweight by water.
 6. The process of claim 1, wherein the startingmaterial of formula I is prepared by the steps of:
 1. treating3-acetylaminoacetephenone of formula IV:

firstly with an alkali metal hydroxide and then with an ethylatingagent, and
 2. reacting the resultingN-(−3-acetylphenyl)-N-ethylacetamide of formula VII:

with an alkyl formate in the presence of an alkali metal alkanolate. 7.The process of claim 6, wherein the alkali metal hydroxide of step 1 ispostassium hydroxide and the ethylating agent of step 1 is ethylbromide.
 8. The process of claim 7, wherein the ethylation of step 1 iscarried out in tetrahydrofuran.
 9. The process of claim 6, wherein thealkali metal alkanoate of step 2 is sodium ethylate.
 10. The process ofclaim 9, wherein the reaction is carried out in tetrahydrofuran.